Pulmonary Nontuberculous Mycobacterial Infection Research Articles

Development and exacerbation of pulmonary nontuberculous mycobacterial infection in patients with systemic autoimmune rheumatic diseases

Objectives: To examine the development and exacerbation of pulmonary nontuberculous mycobacterial (NTM) infection in patients with systemic autoimmune rheumatic diseases (SARD).Methods: We conducted a case–control study. Seventeen of 7013 patients with SARD fulfilling the criteria for pulmonary NTM infection were enrolled in the NTM group. The control group was matched for age, sex, and SARD at a ratio of 2:1.Results: Eight patients with rheumatoid arthritis, four with systemic vasculitis, three with Sjögren’s syndrome, and one each with dermatomyositis and systemic lupus erythematosus were included in the NTM group. Mycobacterium avium was detected in 12 (71%) patients, M. chelonae in 2, and M. intracellulare, M. abscessus, and M. kansasii in 1 patient each. Preexisting lung disease was more common in the NTM group than in the control group (88% versus 38%, p = .0009), particularly bronchiectasis (65% versus 29%, p = .033). The body mass index and serum albumin level were significantly lower in the NTM group than in the control group. Six patients (35%) experienced NTM exacerbation during observation. Clinical immune status at the time of NTM diagnosis, as indicated by the peripheral blood leukocyte/lymphocyte count and serum immunoglobulin G level, was unremarkable and comparable between patients with and without exacerbation, as were the treatments for SARD.Conclusions: In patients with SARD, pulmonary NTM infection may develop and exacerbate without clinically apparent immunosuppression.

Clofazimine inhalation suspension for the aerosol treatment of pulmonary nontuberculous mycobacterial infections

BackgroundNontuberculous mycobacteria are recognized as a concern for cystic fibrosis (CF) patients due to increasing disease prevalence and the potential for detrimental effects on pulmonary function and mortality. Current standard of care involves prolonged systemic antibiotics, which often leads to severe side effects and poor treatment outcomes. In this study, we investigated the tolerability and efficacy of a novel inhaled therapeutic in various mouse models of NTM disease. MethodsWe developed clofazimine inhalation suspension (CIS), a novel formulation of clofazimine developed for inhaled administration. To determine the efficacy, minimum inhibitory concentrations were evaluated in vitro, and tolerability of CIS was determined in naïve mouse models over various durations. After establishing tolerability, CIS efficacy was tested in in vivo infection models of both Mycobacterium avium and M. abscessus. Lung and plasma clofazimine levels after chronic treatments were evaluated. ResultsClofazimine inhalation suspension demonstrated antimycobacterial activity in vitro, with MIC values between 0.125 and 2 μg/ml for M. avium complex and M. abscessus. Administration into naïve mice showed that CIS was well tolerated at doses up to 28 mg/kg over 28 consecutive treatments. In vivo, CIS was shown to significantly improve bacterial elimination from the lungs of both acute and chronic NTM-infected mouse models compared to negative controls and oral clofazimine administration. Clofazimine concentrations in lung tissue were approximately four times higher than the concentrations achieved by oral dosing. ConclusionClofazimine inhalation suspension is a well tolerated and effective novel therapeutic candidate for the treatment of NTM infections in mouse models.

Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research.

Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research.

BCG Vaccination Induces M. avium and M. abscessus Cross-Protective Immunity.

Pulmonary non-tuberculous mycobacterial (NTM) infections particularly caused by Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are becoming major health problems in the U.S. New therapies or vaccines which will help prevent the disease, shorten treatment duration and/or increase treatment success rates are urgently needed. This study was conducted with the objective of testing the hypothesis that Bacillus Calmette Guerin (BCG), a vaccine used for prevention of serious forms of tuberculosis (TB) in children and adolescents in tuberculosis hyperendemic countries, induces cross-protective T cell immunity against Mycobacterium avium (MAV) and MAB. Human TB and NTM cross-protective T cells were quantified using flow cytometric assays. The ability of BCG expanded T cells to inhibit the intracellular growth of MAV and MAB was assessed in co-cultures with infected autologous macrophages. In both BCG-vaccinated and M. tuberculosis (Mtb)-infected mice, NTM cross-reactive immunity was measured using IFN-γ ELISPOT assays. Our results demonstrate the following key findings: (i) peripheral blood mononuclear cells from TB skin test-positive individuals contain MAV and MAB cross-reactive T cells, (ii) both BCG vaccination and Mtb infection of mice induce MAV and MAB cross-reactive splenic cells, (iii) BCG-expanded T cells inhibit intracellular MAV and MAB, (iv) CD4, CD8, and γδ T cells play important roles in inhibition of intracellular MAV and MAB and (v) BCG vaccination of healthy volunteers induces TB and NTM cross-reactive T cells. In conclusion, BCG-vaccination induces NTM cross-reactive immunity, and has the potential for use as a vaccine or immunotherapy to prevent and/or treat pulmonary NTM disease.

Pulmonary nontuberculous mycobacterial infections: presumptive diagnosis based on the international microbiological criteria adopted in the state of São Paulo, Brazil, 2011-2014.

ABSTRACTObjective:Pulmonary nontuberculous mycobacterial infections are caused by nontuberculous mycobacteria (NTM), the microbiological diagnosis of which involves the isolation and identification of the same species in at least two sputum samples, one BAL fluid sample, or one lung biopsy sample. The objective of the present study was to determine the frequency at which the various NTM species are identified among selected individuals and in potential cases of pulmonary nontuberculous mycobacterial infection. Methods:This was a retrospective analysis of the data on species isolated from respiratory specimens collected from 2,843 individuals between 2011 and 2014. Potential NTM infection cases were identified on the basis of the international microbiological criteria adopted in the state of São Paulo. Results:A total of 50 species were identified using the molecular method PCR-restriction enzyme analysis. Samples collected from 1,014 individuals were analyzed in relation to the microbiological criteria, and 448 (44.18%) had a presumptive diagnosis of pulmonary nontuberculous mycobacterial infection, the species identified most frequently being, in descending order, Mycobacterium kansasii, M. abscessus, M. intracellulare, M. avium, and M. szulgai. Conclusions:Although various NTM species were identified among the individuals studied, those presumptively identified most frequently on the basis of the microbiological criteria adopted in the state of São Paulo were the ones that are most commonly associated with pulmonary nontuberculous mycobacterial infection worldwide or in specific geographic regions.

Prevalence and risk factors of pulmonary nontuberculous mycobacterial infections in the Zhejiang Province of China.

Risk factors and prevalence of pulmonary nontuberculous mycobacterial (NTM) diseases were retrospectively evaluated in 1208 suspected pulmonary TB patients seeking care at the Affiliated Hospital of Hangzhou Normal University between July 2018 and December 2018. Further analysis of 390 culture-positive cases demonstrated that 358 (358/390, 91.8%) were infected with Mycobacterium tuberculosis (MTB), 24 (24/390, 6.2%) with NTM and eight (8/390, 2.0%) with both MTB and NTM. M. intracellulare was the most prevalent NTM isolated (16/24, 66.7%), followed by M. abscessus (3/24), M. kansasii (2/24), M. avium (1/24), M. szulgai (1/24) and M. fortuitum (1/24). The difference between NTM and TB case rates for the ⩾65-year-old age group significantly exceeded the difference for the reference group (patients aged 25-44 years) (OR (95% CI): 4.63 (1.03-20.90)). Pulmonary NTM diseases incidence positively correlated with prior TB history (OR (95% CI): 12.92 (3.24-31.82)). Moreover, pulmonary NTM patients were significantly more likely to exhibit underlying bronchiectasis than pulmonary TB patients (OR (95% CI): 18.89 (7.54-47.88)). In conclusion, approximately one-tenth of culture-positive suspected pulmonary TB patients are infected with NTM (most frequently M. intracellulare) in Zhejiang Province, China. The elderly and those with bronchiectasis or a history of TB are at the greatest risk of contracting pulmonary NTM disease.

Association between Inhaled Corticosteroid Use and Pulmonary Nontuberculous Mycobacterial Infection.

Nontuberculous mycobacterial (NTM) pulmonary disease prevalence is increasing. To determine the association between the use of inhaled corticosteroids and the likelihood of NTM pulmonary infection among individuals with treated airway disease. We conducted a case-control study of subjects with airway disease with and without NTM pulmonary infection (based on mycobacterial respiratory cultures) between 2000 and 2010 in northern California. We quantified the use of inhaled corticosteroids, other airway disease medications, and healthcare use within 6 months of NTM pulmonary infection identification. We used 1:10 case-control matching and conditional logistic regression to evaluate the association between the duration and cumulative dosage of inhaled corticosteroid use and NTM pulmonary infection. We identified 248 cases with NTM pulmonary infection with an estimated rate of 16.4 cases per 10,000 subjects treated for airway disease. The median interval between treated airway disease cohort entry (defined as date of patient filling the third airway disease treatment prescription) and NTM case identification was 1,217 days. Compared with control subjects, subjects with NTM pulmonary infection were more likely to use airway disease medications including systemic steroids; they were also more likely to use health care. Any inhaled corticosteroids use between 120 days and 2 years before cohort entry was associated with substantially increased odds of NTM infection. For example, the adjusted odds ratio for NTM infection among inhaled corticosteroid users in a 2-year interval was 2.51 (95% confidence interval, 1.40-4.49; P < 0.01). Increasing cumulative inhaled corticosteroid dose was also associated with greater odds of NTM infection. Inhaled corticosteroid use, and particularly high-dose inhaled corticosteroid use, was associated with an increased risk of NTM pulmonary infection.

MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections.

Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70–95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12–18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.

Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali.

The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.

Comparison of CT Findings of Non-Tuberculous Mycobacterial Pulmonary Infection: Disease Stable versus Progressed Group

Comparison of CT Findings of Non-Tuberculous Mycobacterial Pulmonary Infection: Disease Stable versus Progressed Group

British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD)

Section 4: What is the evidence for transmission of NTM between individuals? Recommendation Section 5: How should the lung disease attributable to NTM infection be defined? Recommendation Good practice point...

Body habitus in patients with and without bronchiectasis and non-tuberculous mycobacteria.

BackgroundFemale gender, tall stature, presence of bronchiectasis are associated with pulmonary nontuberculous mycobacterial (NTM) infections. The biologic relationship between the body habitus and NTM infection is not well defined and the body habitus profile of the patients with NTM and concurrent bronchiectasis is completely unknown.MethodsWe conducted a case control study at the Miami VA Healthcare System and the University of Illinois Medical Center on patients with pulmonary NTM infections between 2010 and 2015. We compared pulmonary NTM subjects with and without bronchiectasis. NTM infection was confirmed by using the American Thoracic Society/ Infectious Disease Society of America criteria. Standard radiological criteria were used to define bronchiectasis in chest CT-scan.ResultsTwo hundred twenty subjects with pulmonary NTM were enrolled in the study. Sixty six subjects (30%) had bronchiectasis on CT scan of the chest. Subjects in the bronchiectasis group included more women (p = 0.002) and were significantly older (p = 0.005). Those patients who had bronchiectasis tended to have a significantly lower weight (less than 50kg) and height ≤155 cm (p <0.0001 and p = 0.018, respectively). Kaplan–Meier analysis confirmed that subjects who had bronchiectasis were shorter and weighed less, after adjusting for gender.ConclusionsThis study defines a new sub-phenotype of NTM subjects with bronchiectasis who tend to be short with lower body weight. Further studies are needed to better understand and define the body habitus profiles of this new sub-phenotype and their clinical implications.

A Breath of Fresh Air for Patients with Pulmonary Nontuberculous Mycobacterial Infection.

A Breath of Fresh Air for Patients with Pulmonary Nontuberculous Mycobacterial Infection.

A haplotype spanning P2X7R, P2X4R and CAMKK2 may mark susceptibility to pulmonary non-tuberculous mycobacterial disease.

Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n=124) and healthy controls (n=229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies >1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p≤0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p<0.0001; R 2 =0.05). Examination of individual alleles within these haplotypes implicated P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease.

Computed Tomography Findings of Pulmonary Mycobacterium simiae Infection.

Nontuberculous mycobacterial (NTM) pulmonary infections can be quite similar to tuberculosis, both clinically and radiologically. However, the treatment protocol is not similar. Mycobacterium simiae is a rare cause of NTM pulmonary infection. Herein, we aimed to evaluate and compare the computed tomography (CT) scan findings of M. simiae infection in lungs. For this reason, thirty-four patients (n = 34) with M. simiae lung infection were retrospectively evaluated. Diagnosis was confirmed by American Thoracic Society (ATS) guidelines and CT scans were reviewed in both lung and mediastinal windows. The average age of patients was 63 ± 14.54 years and 52.9% were male. The majority of patients had cough (91.2%) and sputum production (76.5%). Clinically, 41.2% of patients had previous history of TB (14/34), 38.2% had cardiac diseases (13/34), and 35.3% had diabetes mellitus (12/34). The most common CT findings in our study were nodular lesions (100%) and bronchiectasis (85.29%). Regarding the severity, grade I bronchiectasis was the most prevalent. Other prominent findings were tree-in-bud sign (88.2%), consolidation (52.94%), and lobar fibrosis and volume loss (67.6%). There was no significant zonal distribution of findings. In conclusion, nodular lesions and bronchiectasis are the most frequent features in CT scan of M. simiae pulmonary infection.

The frequency and treatment of pneumothorax associated with pulmonary nontuberculous mycobacterial infection.

Characteristics of pneumothorax associated with nontuberculous mycobacterium (NTM) infection are rarely reported, especially in terms of surgical treatments. Our objectives were to show the tendency and clinical courses of pneumothorax due to NTM and discuss the way of therapy in our hospital. We retrospectively analyzed 557 patients with NTM infection over a period of 5years at the Nagara Medical Center. A total of 12 out of the 557 patients (2.2%) suffered from pneumothorax caused by NTM infection without other pulmonary diseases. The diagnosis of all NTM cases was mycobacterium avium complex. Of these 12 patients, three required observation only (25%), five required drainage only (42%), and four required surgery after drainage (33%). The four surgically treated patients suffered from empyema as well as pneumothorax. They were in worse nutritional condition than non-surgically treated patients. For the patients requiring surgery, we selected reasonable surgical methods; we sutured the fistula of lung in all cases and covered it with muscle or omentum or polyglycolic acid sheets without a case in which endobronchial embolization was performed in advance before surgery. Finally, all pneumothorax healed. Thereafter, three of these four patients took unfavorable courses: progressing malnutrition, complications worsening or contralateral pneumothorax. We should select an appropriate treatment including surgery against NTM-associated pneumothorax without losing an opportunity because of its intractability and exhausting effect.

Not Just Lady Windermere: Epidemiology of Non-Tuberculous Mycobacterial Pulmonary Infections at a Community-Based Health System

Not Just Lady Windermere: Epidemiology of Non-Tuberculous Mycobacterial Pulmonary Infections at a Community-Based Health System

Stability and Consistency of Treatment Effect With Liposomal Amikacin for Inhalation (LAI) as Add-on Therapy in Patients With Pulmonary Nontuberculous Mycobacterial (PNTM) Infection

Stability and Consistency of Treatment Effect With Liposomal Amikacin for Inhalation (LAI) as Add-on Therapy in Patients With Pulmonary Nontuberculous Mycobacterial (PNTM) Infection

Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections.

Pulmonary infections with nontuberculous mycobacteria (P-NTM), such as by Mycobacterium avium complex (M. avium), are increasingly found in the elderly, but the underlying mechanisms are unclear. Recent studies suggest that adaptive immunity is necessary, but not sufficient, for host defense against mycobacteria. Heme oxygenase-1 (HO-1) has been recognized as a critical modulator of granuloma formation and programmed cell death in mycobacterial infections. Old mice (18-21 mo) infected with M. avium had attenuated HO-1 response with diffuse inflammation, high burden of mycobacteria, poor granuloma formation, and decreased survival (45%), while young mice (4-6 mo) showed tight, well-defined granuloma, increased HO-1 expression, and increased survival (95%). To further test the role of HO-1 in increased susceptibility to P-NTM infections in the elderly, we used old and young HO-1+/+ and HO-1-/- mice. The transcriptional modulation of the JAK/STAT signaling pathway in HO-1-/- mice due to M. avium infection demonstrated similarities to infected wild-type old mice with upregulation of SOCS3 and inhibition of Bcl2. Higher expression of SOCS3 with downregulation of Bcl2 resulted in higher macrophage death via cellular necrosis. Finally, peripheral blood monocytes (PBMCs) from elderly patients with P-NTM also demonstrated attenuated HO-1 responses after M. avium stimulation and increased cell death due to cellular necrosis (9.69% ± 2.02) compared with apoptosis (4.75% ± 0.98). The augmented risk for P-NTM in the elderly is due, in part, to attenuated HO-1 responses, subsequent upregulation of SOCS3, and inhibition of Bcl2, leading to programmed cell death of macrophages, and sustained infection.

Enlarged Dural Sac in Idiopathic Bronchiectasis Implicates Heritable Connective Tissue Gene Variants

Patients with idiopathic bronchiectasis are predominantly female and have an asthenic body morphotype and frequent nontuberculous mycobacterial respiratory infections. They also demonstrate phenotypic features (scoliosis, pectus deformity, mitral valve prolapse) that are commonly seen in individuals with heritable connective tissue disorders. To determine whether lumbar dural sac size is increased in patients with idiopathic bronchiectasis as compared with control subjects, and to assess whether dural sac size is correlated with phenotypic characteristics seen in individuals with heritable connective tissue disorders. Two readers blinded to diagnosis measured anterior-posterior and transverse dural sac diameter using L1-L5 magnetic resonance images of 71 patients with idiopathic bronchiectasis, 72 control subjects without lung disease, 29 patients with cystic fibrosis, and 24 patients with Marfan syndrome. We compared groups by pairwise analysis of means, using Tukey's method to adjust for multiple comparisons. Dural sac diameter association with phenotypic and clinical features was also tested. The L1-L5 (average) anterior-posterior dural sac diameter of the idiopathic bronchiectasis group was larger than those of the control group (P < 0.001) and the cystic fibrosis group (P = 0.002). There was a strong correlation between increased dural sac size and the presence of pulmonary nontuberculous mycobacterial infection (P = 0.007) and long fingers (P = 0.003). A trend toward larger dural sac diameter was seen in those with scoliosis (P = 0.130) and those with a family history of idiopathic bronchiectasis (P = 0.149). Individuals with idiopathic bronchiectasis have an enlarged dural sac diameter, which is associated with pulmonary nontuberculous mycobacterial infection, long fingers, and family history of idiopathic bronchiectasis. These findings support our hypothesis that "idiopathic" bronchiectasis development reflects complex genetic variation in heritable connective tissue and associated transforming growth factor-β-related pathway genes.